Non-steroidal anti-inflammatory drugs (NSAIDs) are compounds used extensively for the treatment of inflammatory conditions, including pain-releasing, anti-pyretic and rheumatoid arthritis. The combined analgesic and anti-inflammatory effects of NSAIDs make them particularly useful for the symptomatic relief of painful and/or inflammatory conditions including musculoskeletal and joint disorders, such as rheumatoid arthritis, osteoarthritis, spondylo arthopathic, peri-articular and soft tissue disorder. NSAIDs are believed to inhibit the enzyme cyclooxygenase (COX) that is involved in the biosynthesis of prostaglandins G and H from arachidonic acid. Prostaglandins (PGs) are ubiquitous fatty acid derivatives that serve as autocrine/paracrine mediators involved in many different physiological processes in addition to their well recognized role in inflammation and immune response modulation. Prostaglandins elicit a variety of important and beneficial responses. Among the undesirable properties of Prostaglandins is their ability to induce pain, fever, and symptoms associated with the inflammatory response. NSAIDS exert their actions primarily by inhibiting the production of PGs. Recent studies of inflammatory processes has led to the identification of the key enzyme COX that is expressed in inflammatory conditions. So far two isozymes of COX are known: COX-1 and COX-2. COX-1 is constitutively produced in a variety of tissues and appears to be important to the maintenance of normal physiological functions, including gastric and renal cytoprotection. COX-2 is an inducible isozyme, which is produced in cells under the stimulation of endotoxins, cytokines, and hormones and catalyzes or regulates the production of prostaglandins which cause inflammation. The prostaglandins synthesized by COX-2 are mediators of inflammation, the body's response to injury characterized by increased blood flow to the tissue, increased temperature, redness, accumulation of immune cells and pain. COX-2 and prostaglandins are also involved in the spread of tumors, such as in colon cancer. COX-2 is over-expressed in colon cancer tissue. COX-2 inhibitors possess potential prophylactic and therapeutic application to colon cancer. They reduce the rate of cell death, increase the invasiveness of the malignancies and promote the growth of blood vessels that deliver nourishment to the lesions. Currently, drugs that inhibit COX-2 are prescribed in the treatment of pre-cancerous polyps in the colon and colon cancer, where cells have increased levels of the enzyme. Moreover, it has been shown that an inflammatory process in brain cells may contribute to Alzheimer's disease (AD) damage and that several compounds and processes known to be involved in inflammation can be found in and around AD plaques (dense, insoluble protein deposits that are found outside and around the brain's nerve cells and are associated with AD). If these processes contribute to the death of neurons, it has been proposed that suppressing the inflammatory activity, by using NSAIDs, should slow the rate of progression of AD.
The current therapeutic use of NSAIDs, however, has been associated with the inhibition of both COX-1 and COX-2 and causes well-known side effects at the gastrointestinal and renal level. Therefore, the selective COX-2 inhibitors could provide anti-inflammatory agents devoid of the undesirable effects associated with classical, nonselective NSAIDs. Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase. The discovery of an inducible enzyme associated with inflammation COX-2 or “prostaglandin G/H synthase II” has provided a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects related to inhibition of COX-1. The COX-2 inhibitors as selective anti-inflammatory drugs are chemically aminosulfonylaryl or methylsulfonylaryl-containing substances, such as Nimesulide (R. H. Brogen and A. Ward. Drugs, 1998, 36: 732-753), NS-398 (JP 1990000268, JP 1990300122), Meloxicom (DE 2756113), pyrrazole-containing tricyclic compounds, for example, Celecoxib (WO 96/41825, WO 96/41626), oxazole-containing tricyclic compounds, for example, JRE-522 (EP 0745596), unsaturated gamma-lactone-containing compounds, for example, Rofecoxib (EP 0788476). The non-selective NSAID Indomethacin as a lead compound was chemically modified to give rise to selective COX-2 inhibitors without sulfonyl groups, for example L-748780 and L-761066 (W. C. Black et al. Bioorg Med. Chem. Lett. 1996, 6: 725-742,). These compounds exhibit selective COX-2 inhibition activity at differing levels and constitute a group of anti-inflammatory drugs with little adverse reactions. However, a need still exists for novel compounds, pharmaceutical compositions and methods for effectively inhibiting COX-2.